This tutorial review presents a description of the controlling elements of intermolecular C-H functionalization by means of C-H insertion by donor/acceptor rhodium carbenes. These rhodium carbenes, readily derived from the combination of diazo compounds with dirhodium(ii) catalysts, are sufficiently reactive to undergo a wide range of C-H insertions. They are also capable of highly selective reactions, controlled by a combination of steric and electronic factors. An overview of the structural factors that influence site selectivity will be given, followed by a description of the exceptional diastereo- and enantioselectivity that can be achieved. Several examples will be shown of how this methodology can be applied to streamline the synthesis of natural products and pharmaceutical targets.

Intermittent fasting (IF) protects against the development of metabolic diseases and cancer, but whether it can prevent diabetic microvascular complications is not known. In mice, we examined the impact of long-term IF on diabetic retinopathy (DR). Despite no change in glycated hemoglobin, mice on the IF regimen displayed significantly longer survival and a reduction in DR end points, including acellular capillaries and leukocyte infiltration. We hypothesized that IF-mediated changes in the gut microbiota would produce beneficial metabolites and prevent the development of DR. Microbiome analysis revealed increased levels of Firmicutes and decreased Bacteroidetes and Verrucomicrobia. Compared with mice on ad libitum feeding, changes in the microbiome of the mice on IF were associated with increases in gut mucin, goblet cell number, villi length, and reductions in plasma peptidoglycan. Consistent with the known modulatory effects of Firmicutes on bile acid (BA) metabolism, measurement of BAs demonstrated a significant increase of tauroursodeoxycholate (TUDCA), a neuroprotective BA, in on IF but not in on AL feeding. TGR5, the TUDCA receptor, was found in the retinal primary ganglion cells. Expression of TGR5 did not change with IF or diabetes. However, IF reduced retinal TNF-α mRNA, which is a downstream target of TGR5 activation. Pharmacological activation of TGR5 using INT-767 prevented DR in a second diabetic mouse model. These findings support the concept that IF prevents DR by restructuring the microbiota toward species producing TUDCA and subsequent retinal protection by TGR5 activation.

No abstract

Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC50 values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC50 values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme–substrate/exemestane complexes. The observed structure–activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.

No abstract

No abstract

C–H functionalization is a very active research field that has attracted the interest of scientists from many disciplines. This Outlook describes the collaborative efforts within the NSF CCI Center for Selective C–H Functionalization (CCHF) to develop catalyst-controlled selective methods to enhance the synthetic potential of C–H functionalization.

Background Brain imaging and behavioral studies suggest an inverse relationship between dopamine (DA) D2/D3 receptors and vulnerability to cocaine abuse, though most research has utilized males. For example, male monkeys that become dominant in a social group have significant elevations in D2/D3 receptor availability and are less vulnerable to cocaine reinforcement. Methods DA D2/D3 receptor availability was assessed in female cynomolgus monkeys (n=16) using positron emission tomography (PET) while they were individually housed, 3 months after stable social hierarchies had formed and again when individually housed. In addition, PET was used to examine changes in DA transporter (DAT) availability following social hierarchy formation. After imaging studies were complete, monkeys were implanted with indwelling intravenous catheters and self-administered cocaine (0.001–0.1 mg/kg/injection) under a fixed-ratio 30 schedule of reinforcement. Acquisition of cocaine reinforcement occurred when response rates were significantly higher than when saline was self-administered. Results Neither DAT nor D2/D3 receptor availability in the caudate nucleus and putamen was predictive of social rank, but both significantly changed following formation of social hierarchies. D2/D3 receptor availability significantly increased in females that became dominant, while DAT availability decreased in subordinate females. Dominant female monkeys acquired cocaine reinforcement at significantly lower doses than subordinate monkeys. Conclusions Based on these findings, the relationship between D2/D3 receptor availability and vulnerability to cocaine reinforcement appears opposite in females and males. These data indicate that the social environment profoundly affects the DA system, but does so in ways that have different functional consequences for females than males.